l to a severity of scarring that eliminates vision completely," said Nathans. FEVR is known to arise from defects in a gene known as Frizzled-4, which codes for a protein receptor (Fz4). Although Nathans and his colleagues had studied the Frizzled-4 gene and the Fz4 protein, they did not know what that external signal was, he said. The first hints that the two diseases might be functionally related came when the researchers observed intriguing similarities in the blood vessel defects in the two disorders in mice lacking the responsible genes. These vessel pathologies occurred in both the eye and the inner ear.

"While there was a clinical similarity, the two diseases were far from identical, because FEVR patients have a much milder version of the problem," said Nathans. Also, he said, people with Norrie disease show progressive deafness, while those with FEVR do not. "In speculating about how the pieces of the puzzle of the two diseases might fit together, we thought the idea of a direct relationship seemed kind of crazy -- but not too crazy. So, we decided to try a few experiments that might reveal that link. Within a month we had the answer." The researchers conducted cell culture experiments using techniques to trace the interaction of the proteins, which revealed that together the Norrin and Fz4 proteins activate a key development pathway called the Wnt pathway. The two components also required a third co-receptor called Lrp5, which is known to be key to Wnt signaling, said Nathans.

The cell culture experiments also revealed that the Norrin protein was a key trigger for the Fz4 receptor, selectively binding to it and activating it. "Importantly, we found this to be very high-affinity, highly specific binding," noted Nathans.

Further, the researchers studied two human forms of FEVR, finding that in patients with the disorder, mutations in the Frizzled-4 gene interfered with Norrin-dependent signaling.

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Contact: Jim Keeley
keeleyj@hhmi.org
301-215-8858
Howard Hughes Medical Institute
18-Mar-2004

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